title: Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25.
abstract: Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 microg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-alpha (sIL-2R-alpha) and soluble beta2-microglobulin (beta2mu) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-alpha and beta2mu levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Ju
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000107:Acetylation; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000077561:Daclizumab; D047630:Depsipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006657:Histones / Q000378:metabolism; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020714:Maximum Tolerated Dose; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015996:Survival Rate
chemical_list: D017304:Annexin A5; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047630:Depsipeptides; D006657:Histones; C508018:Il2ra protein, mouse; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D000077561:Daclizumab; D053148:Caspase 3; D053453:Caspase 9